Aromatic amides, preparation method and application as medicines

ABSTRACT

A compound having a formulawherein the substituents are defined as in the specification and its non-toxic, pharmaceutically acceptable acid addition salts which are useful as antibiotics.

This application is a 371 of PCT/FR99/00014 filed Jan. 7, 1999.

The present invention relates to new aromatic amides, their preparationprocess and their use as medicaments.

A subject of the invention is the compounds of formula (I):

in which:

Y represents an oxygen atom, or an N-Nalk₁ or NOalk₂ radical in whichalk₁ and alk₂ represent an alkyl radical, containing up to to 12 carbonatoms optionally interrupted by one or more oxygen, sulphur or nitrogenatoms, optionally substituted by one or more halogen atoms, by an arylradical optionally substituted by one or more halogen atoms, by aheterocyclic radical, by one or more

radicals in which Ra and Rb identical or different from one anotherrepresent a hydrogen atom, an optionally substituted alkyl radicalcontaining up to 8 carbon atoms, or Ra and Rb form together with thenitrogen atom to which they are joined to heterocycle which can containin addition another heteroatom chosen from oxygen, sulphur or nitrogen,X represents a hydrogen atom, a hydroxyl radical, a linear, branched orcyclic alkyl, alkenyl or alkynyl radical optionally interrupted by oneor more oxygen, sulphur and or nitrogen atoms, containing up to 12carbon atoms, optionally substituted by one or more halogen atoms, by aheterocyclic radical, one or more free or esterified OH, C≡N, NO₂,

radicals in which Ra and Rb, identical or different, represent ahydrogen atom, an alkyl radical containing up to 8 carbon atoms, or Raand Rb form together with the nitrogen atom to which they are linked aheterocycle optionally containing another heteroatom chosen fromnitrogen, sulphur or oxygen, or X represents an alkoxy radical or a

radical in which Re represents an alkyl radical containing up to 8carbon atoms, optionally substituted by one or more of the substituentsindicated above, or X represents an NRcRd radical in which Rc and Rdidentical or different, represent a hydrogen atom or an alkyl radicalcontaining up to 12 carbon atoms, optionally substituted by one or moreof the substituents indicated above, or Rc and Rd form together with thenitrogen atom to which they are linked a heterocycle optionallycontaining another heteroatom chosen from nitrogen, sulphur or oxygen,

Z represents a hydrogen or halogen atom or a free, etherified oresterified OH radical,

R₂ represents a hydrogen or halogen atom,

R₃ represents a hydrogen atom, an alkyl radical containing up to 8carbon atoms or a halogen atom,

R represents a hydrogen atom or an alkyl radical containing up to 4carbon atoms,

R₁ represents a hydrogen atom, a linear, branched or cyclic alkyl,alkenyl or alkynyl radical containing up to 8 carbon atoms, optionallysubstituted by one or more halogen atoms, a C≡N radical, an aryl radicalcontaining up to 14 carbon atoms,

R₅ represents a hydrogen atom, an O-alkyl radical containing up to 4carbon atoms,

either R₆ represents an alkyl or CH₂ —O—alkyl radical, in which alkylrepresents an alkyl radical containing up to 8 carbon atoms,

R₇ represents a hydrogen atom or an alkyl radical containing up to 8carbon atoms,

or R₆ and R₇ form together with the carbon atom which they carry a ringcontaining up to 8 carbon atoms, as well as the salts of the compound offormula (I), when the compounds of formula (I) have a basic function.

As examples of salts there can also be mentioned the salts formed withthe following acids: acetic, propionic, trifluoroacetic, maleic,tartaric, methanesulphonic, benzenesulphonic, paratoluenesulphonic,hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric andespecially stearic, ethylsuccinic or laurylsulphonic acids.

In the definition of the substituents:

the alkyl, alkeny or alkynyl radical is preferably a methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl,allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical,

the halogen is preferably fluorine or chlorine, or bromine,

the aryl radical is preferably the phenyl radical,

the heterocyclic radical is preferably the pyrrolyl, pyrrolidinyl,pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl,oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl,triazolyl, thiazolyl, azetidinyl, aziridinyl radical.

A more particular subject of the invention is the compounds of formula(I) in which Y represents an oxygen atom, those in which Y represents anNO-alkyl radical in which the alky radical contains up to 4 carbonatoms, for example those in which Y represents the NOC₂H₅ radical.

Among the preferred compounds of the invention there can be mentionedthe compounds of formula (I) in which X represents an alkyl radicalcontaining up to 4 carbon atoms and in particular the CH₃ radical, oralso those in which X represents an NH₂ radical, or also those in whichX represents the:

radical.

Among the preferred compounds of the invention, there can be mentionedthe compounds of formula (I) in which R₁ represents a

radical

those in which R represents a hydrogen atom, or also those in which R₃represents a methyl radical, or also those in which Z represents ahydrogen atom, or also those in which R₂ represents a hydrogen atom, oralso those in which R₅ represents an OCH₃ radical, or also those inwhich R₆ represents a methyl radical, or also those in which R₇represents a methyl radical, those in which R₇ represents an ethylradical, those in which R₆ and R₇ form with the carbon which carriesthem a cyclopentyl radical.

Among the preferred compounds of the invention, there can be mentionedthe compounds whose preparation is given hereafter in the experimentalpart and quite particularly the compounds of 1, 2, 3, 4, 5 and 9.

The products of general formula (I) have a very good antibiotic activityon gram ^(⊕)bacteria such as staphylococci, streptococci, pneumococci,enterococci, listeria, anaerobes.

The compounds of the invention can therefore be used as medicaments inthe treatment of germ-sensitive infections and in particular, in that ofstaphylococcia such as staphylococcal septicaemias, malignantstaphylococcia of the face or skin, pyodermitis, septic or suppuratingwounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococciasuch as primitive or post-influenzal acute angina, bronchopneumonia,pulmonary suppuration, streptococcia such as acute agina, otitis,sinusitis, scarlatina, pneumococcia such as pneumonia, bronchitis anddiphtheria. The products of the present invention are also activeagainst infections caused by germs such as Haemophilus influenzae.

Therefore a subject of the invention is the compounds of formula (I) asmedicaments.

A more particular subject of the invention is, as medicaments, thecompounds indicated above as preferred compounds.

A subject of the invention is also the pharmaceutical compositionscontaining at least one of the medicaments defined above as activeingredient.

These compositions can be administered by buccal, rectal, parenteralroute, or by local route as a topical application on the skin and mucousmembranes, but the preferred administration route is the buccal orinjectable route.

They can be solids or liquids and be presented in the pharmaceuticalforms commonly used in human medicine, such as for example, plain orsugar-coated tablets, gelatin capsules, granules, suppositories,injectable preparations, ointments, creams, gels; they are preparedaccording to the usual methods. The active ingredient or ingredients canbe incorporated with the excipients usually used in these pharmaceuticalcompositions such as talc, gum arabic, lactose, starch, magnesiumstearate, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,various wetting, dispersing or emulsifying agents, preservatives.

These compositions can also be presented in the form of a powderintended to be dissolved extemporaneously in an appropriate vehicle, forexample, apyrogenic sterile water.

The does administered is variable according to the affection treated,the patient in question, the administration route and the productconsidered. It can be, for example, comprised between 50 mg and 3000 mgper day by oral or injectable route for an adult for the preferredproducts.

A subject of the invention is also a process for the preparation of thecompounds of formula (I), characterized in that a compound of formula(II):

in which the radicals R₂, R₃, Z, R₅, R₆ and R₇ retain their previousmeaning, OW represents a blocked hydroxyl group and W′ represents analkyl or Oalkyl radical containing up to 4 carbon atoms, is subjected

to the action of an agent capable of introducing the

radical

or of a series of operations capable of introducing the

radical

R and R₁ retaining their previous meaning,

to the action of an agent capable of releasing the hydroxyl radical fromthe OW radical,

to the optional action of an agent capable of replacing W′ by the Xradical which is different from alkyl or Oalkyl,

to the optional action of an agent capable of introducing the Y radicalwhich is different from oxygen,

to the optional action of a salification agent.

The products of formula (II) used at the start of the process of theinvention are new products, the preparation of certain products offormula (II) is given hereinafter in the experimental part.

The other products of formula (II) can be synthesized by analogy withthe processes described in the experimental part.

A more particular subject of the invention is the compounds of formula(II) the preparation of which is given in the experimental part.

In a preferred embodiment:

The introduction of the

radical is carried out in several stages, firstly the action of asubstituted or unsubstituted phenylchloroformate, then the action of acompound of formula R₁ONHR in which R₁ and R retain their previousmeaning

the OH group is blocked in the form of a tetrahydropyrane,

the release of the hydrolysis by acid hydrolysis, for example by theaction of paratoluenesulphonic acid,

the optional conversion of the W′ radical to the X radical and theconversion of the Y radical is carried out according to the standardprocesses. For the Y radical, it is in particular the action of anamine.

A subject of the invention is also a process characterized in that theproduct of formula (II) is prepared by the action of a compound offormula (III)

in which R₅, R₆ and R₇ retain their previous meaning on a compound offormula (IV)

in which R₂, R₃ and Z retain their previous meaning, then of a blockingagent of the free hydroxyl radical. The following compounds of formula(III) are new and are in themselves a subject of the present invention,namely:

The following examples illustrate the invention without however limitingit.

Preparation 1: ethyl7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyrane-3-carboxylateSTAGE A: ethyl7-[(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranousyl)oxy]-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyrane-3-carboxylate

A solution containing 80 g of ethyl7-hydroxy-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyrane-3-carboxylatein 1200 ml of methylene chloride is agitated under an argon atmosphere.52.07 g of 6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranose and 71.22 gof triphenyl-phosphine are added at 0° C.

54.78 ml of diisopropyl azocarboxylate is introduced at 0° C. After onehour of reaction at ambient temperature, 34 g of triphenylphosphine and25.6 ml of diisopropyl azocarboxylate are added again. Agitation iscarried out for 16 hours at ambient temperature followed by evaporationto one-half volume and filtering the suspension eluting with thetoluene/isopropyl alcohol mixture (95-5). When the product starts topass through, a mixture with 6% isopropyl alcohol is carried out. Aftersaponification in 700 ml of hexane/ethyl acetate mixture (4-5), 64.4 gof sought product is obtained that is used as it is in the followingstage.

STAGE B: ethyl7-[(6-deoxy-5-C-methyl-4-O-methyl-3-O-(triethylsilyl)-alpha-L-lyxo-hexopyranosyl)oxy]-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyrane-3-carboxylate

50 g of a solution from stage A in 500 ml of methylene chloride isagitated under argon at ambient temperature. 42 ml ofdiisopropylethylamine and 9.66 g of imidazole are added. The solution isagitated for 15 minutes or cooled down to 0° C., 20.64 ml oftriethylchlorosilane is added dropwise over 30 minutes, and agitation iscarried out for 2 hours at 0° C. The reaction medium is poured into amolar solution of sodium dihydrogen phosphate. Extraction is carried outwith methylene chloride followed by drying and evaporating to dryness.66.27 g of product is recovered that is purified on silica eluting witha methylene chloride mixture at 0.75% of acetone. When the product isnearly isolated, eluting is carried out with a methylene chloridesolution at 1% of acetone. 41.04 g of sought product is obtained aftersaponification in a hexane/ethyl acetate mixture (9-1). NMR 1H (300 MHz,CDC13, ppm)

0.73 (q, 6H), 1.04 (t, 9H), 1.04 (s, 3H), 1.30 (s, 3H), 1.40 (t, 3H),2.24 (s, 3H), 2.74 (d, J=1 Hz, mobile 1H), 3.28 (d, 1H, J=9), 3.53 (s,3H), 4.05 (M, 1H), 4.27 (dd, 1H, J=3.5 and 9 Hz), 4.43 (q, 2H), 5.31 (s,2H), 5.62 (d, 1H, J=2 Hz), 7.12 (d, 1H, J=9 Hz), 7.43 (m, 5H), 7.63 (d,1H, J=9 Hz).

STAGE C: ethyl7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-3-O-(triethylsilyl)-alpha-L-lyxo-hexopyranosyl]oxy]-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyrane-3-carboxylate

A solution containing 40.9 g of product of the previous stage in 400 mlof methylene chloride is agitated under argon at ambient temperature. Afew drops of paratoluene sulphonic acid, then 11.54 ml of dihydropyraneare added. Agitation is carried out for 2 hours at ambient temperature.6 g of bisodium carbonate is added. The suspension is agitated for 15minutes followed by diluting with 1000 ml of a hexane/ethyl acetatemixture (2-1) and pouring onto water. The reaction mixture is decanted,the organic phase is dried over sodium sulphate and evaporated todryness. 54.67 g of product is obtained that is purified eluting with ahexane/ethyl acetate mixture (4-1). 36.83 g of product is thus obtained.

STAGE D: ethyl7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-3-O-(triethylsilyl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyrane-3-carboxylate

18 g of product prepared in the previous stage are hydrogenated insolution in 360 ml of tetrahydrofurane in the presence of 0.240 g ofpalladium on carbon followed by filtering. The catalyst is washed with alittle tetrahydrofurane. 100 ml of solvent is evaporated and a solutionis obtained which is used as it is in the following stage.

STAGE E: ethyl7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyrane-3-carboxylate

A solution containing 15.31 g of product from the previous stage in 250ml of tetrahydrofurane is cooled down under argon to 0° C. 31 ml oftetrabutylammonium fluoride (1M in THF) is added dropwise. The reactionmedium is diluted with 400 ml of a hexane/ethyl acetate mixture (1-2).300 ml of a solution of 10% of sodium hydrogen sulphate is addedfollowed by decanting, drying and evaporating to dryness. The crudeproduct obtained is solubilized in 20 ml of ethyl ether. The reactionmedium is cooled down to −10° C. and 80 ml of pentane is added underagitation. The suspension obtained is agitated at −20° C., followed byfiltering at −16° C. The product obtained is washed with the pentane anddried. 9.4 g of sought product is obtained.

Preparation 2:3-acetyl-7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2H-1-benzopyrane-2-oneSTAGE A:4-(diphenylmethoxy)-8-methyl-7-(tetrahydro-2H-pyrane-2-yl)-2H-1-benzopyrane-2one

55 g ofhydroxy-8-methyl-7-(tetrahydro-2H-pyrane-2-yl)-2H-1-benzopyrane-2-one isadded to 250 ml of anhydrous dimethylformamide heated to 40° C., and asolution of 58.3 g of diphenyldiazomethane in 250 ml of dimethylformamide is added dropwise. The addition is carried out over 3 hourswhilst maintaining the temperature at 40° C.

Several portions of 3 g of diphenyldiazomethane are added again andagitation is carried out for one hour at 40° C.

The reaction medium is poured into 2 l of sulphuric ether. The organicsolution is washed with an aqueous solution of sodium bicarbonate, withsolution of soda (0.1 M), with water and salt water followed byevaporation to dryness. The residue is agitated in an isopropylether-hexane mixture (1-2). The insoluble part is separated and dried.20.5 g of sought product is obtained.

CCM CH₂Cl₂—AcOEt (95-5). Rf=0.44.

STAGE B: 4-(diphenylmethoxy)-7-hydroxy-8-methyl-2H-1-benzopyrane-2-one

35 ml of a 0.9 M solution of hydrochloric acid in methanol are added toa solution containing a mixture of 20 g of the product of stage A, 100ml of dichloromethane and 100 ml of methanol. Agitation is carried outfor 2 hours at ambient temperature and the solvents are evaporated. Theresidue is taken up in absolute ethanol cooled down to 0° C. Theinsoluble part is separated and rinsed with ice cold alcohol then withsulphuric ether followed by drying. 15.53 g of product is recoveredwhich is taken up in ether, separated and dried. 14.54 g of soughtproduct is obtained. NMR 1H (300 MHz, CDCl₃, ppm)

2.31 (s, 3H), 5.62 (s, 1H), 6.35 (s, 1H), 6.78 (d, 1H, J=_Hz), 7.75 (d,1H, J=_Hz), 6.99 to 7.10 (m, _H), 7.30 to 7.42 (m, _H).

STAGE C:7-[(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy]-4-(diphenylmethyl)-8-methyl-2H-1-benzopyrane-2-one

A mixture of 91.13 g of the product of stage B, 58.6 g of6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranose and 80 g oftriphenylphoshine in 900 ml of dichloromethane are cooled down to 0° C.60 ml of diisopropylazodicarboxylate is added dropwise. Agitation iscarried out for 1 hour at ambient temperature.

34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate areadded. Agitation is carried out for 1 hour at ambient temperature. 34 gof triphenylphosphine and 25 ml of diisopropylazodicarboxylate are addedand agitation is carried out for 12 hours at ambient temperature.Concentration is carried out under reduced pressure. Chromatograph iscarried eluting with a toluene/isopropyl alcohol mixture (95-5). Aftercombining the fractions and evaporation of the solvents, 86.83 g ofsought product is recovered after recrystallization from isopropylether. NMR 1H (300 MHz, CDCl₃, ppm)

1.13 (s, 3H), 1.37 (s, 3H), 2.24 (s, 3H), 2.69 (s, 1H), 2.79 (s, 1H),3.38 (d, 1H, J=10 Hz), 3.60 (s, 3H), 4.24 (m, 1H), 4.28 (m, 1H), 5.56(s, 1H), 5.64 (d, 1H, J=1.5 Hz), 6.35 (s, 1H), 7.18 (d, 1H), 7.81 (d,1H), 7.39 (m, 10 H).

STAGE D:7-[[6-deoxy-5-C-methyl-4-O-methyl-3-O-(triethylsilyl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-(diphenylmethoxy)-8-methyl-2H-1-benzopyrane-2-one

26.6 g of imidazole and 70.15 ml of diisopropylethylamine are added to asolution cooled down to 0° C., containing 80 g of the product of theprevious stage and 600 ml of dichloromethane. 33.5 ml of triethylsilylchloride is added dropwise. Agitation is carried out for 1 hour atambient temperature followed by washing with an aqueous solution ofsodium dihydrogen phosphate (1M), with water and with salt water, dryingover magnesium sulphate, filtering and concentration. 97.58 g of productis recovered which is purified by chromatography on silica eluting withthe dichloromethane acetone mixture (0.8 to 1%). 46.5 g of product isobtained. NMR 1H (300 MHz, CDCl₃-d6, ppm)

0.60 (q, _H, J=_Hz), 0.74 (q, _H, J=_Hz), 0.97 (t, _H, J=_Hz), 1.00 (t,_H, J=_Hz), 1.10 (s, 3H), 1.32 (s, 3H), 2.24 (s, 2H), 2.74 (s, 1H), 3.31(d, 1H, J=_Hz), 3.54 (s, 3H), 4.07 (m, 1H), 4.29 (dd, 1H, J=_Hz), 5.50(s, 1H), 5.64 (d, 1H, J=_Hz, 6.35 (s, 1H), 7.28 (d, 1H, J=_Hz), 7.81 (d,1H, J=_Hz), 7.40 (m).

STAGE E:7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-3-O-(triethylsilyl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-(diphenylmethoxy)-8-methyl-2H-1-benzopyrane-2-one

19 ml of dihydropyrane and 400 mg of paratoluene sulphonic acid (PTSA)are added to a solution containing 67 g of the product of the previousstage and 1 l of dichloromethane. Agitation is carried out for 40minutes at ambient temperature, 300 mg of PTSA is added. After 30minutes, 100 mg of PTSA is added, then another 100 mg of PTSA. Agitationis carried out for 20 more minutes, then finely ground sodium hydrogencarbonate is introduced. Agitation is carried out for 10 minutes, thereaction medium is diluted with a hexane/ethyl acetate mixture (1-2),washed with water and with salt water followed by drying, filtering andevaporating the solvents. The product obtained is chromatographedeluting with a heptane/ethyl acetate mixture (4-1). 77.9 g of soughtproduct is recovered. NMR 1H (300 MHz, DMSO-d6, ppm)

0.64 (q, _H, J=_Hz), 0.73 (q, _H, J=_Hz), 0.95 to 1.32 (_H), 2.25 (s,_H), 2.27 (s, _H), 3.30 (d, _H, J=_Hz), 3.4 (d, _H, J=_Hz), 3.50 (m, 2H,3.93 (m, 2H), 3.53 (s, _H), 3.54 (s, _H), 4.04 to 4.15, 4.36 (dd, _H),J=_Hz), 4.94 (l), 4.96 (l), 5.50 (sl, _H), 5.65 (bs), 6.37 (s, 1H), 7.15(d, _H, J=_Hz), 7.19 (d, _H, J=_Hz), 7.81 (m, 1H), 7.30 to 7.44, 1.47 to2.00.

STAGE F:7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-3-O-trimethylsilyl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2H-1-benzopyrane-2-one

15 g of the product of the previous stage is hydrogenated in 150 ml ofabsolute ethanol in the presence of palladium on carbon (2 g, 10%). Thecatalyst is eliminated by filtration and the solvents are evaporated todryness. 14.4 g of produce is obtained.

STAGE G:3-acetyl-7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-3-O-(triethylsilyl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2H-1-benzopyrane-2-one

6.52 g of dimethylaminopyridine are added to a solution containing 14.37g of the product of the previous stage and 150 ml of dichloromethane.2.72 ml of acetic anhydride is introduced dropwise. Agitation is carriedout at ambient temperature under argon for 1 hour followed by dilutingwith 200 ml of dichloromethane, washing with an aqueous solution ofsodium dihydrogen phosphate, drying over magnesium sulphate, filteringand concentrating. 14.9 g of sought product is obtained.

STAGE H:3-acetyl-7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2H-1-benzopyrane-2-one

27 ml of a 1M solution of tetrabutylammonium fluoride intetrahydrofurane is introduced dropwise at 0° C. to a solutioncontaining 15.2 ml of product of the previous stage in 250 m of THF.Agitation is carried out under argon for 48 hours at ambienttemperature. The medium is diluted with an ethyl acetate/hexane mixture,washed with water and with salt water followed by drying, filtering andconcentrating to dryness. 13 g of a product is obtained which istriturated in pentane, the supernatant is eliminated and the operationis repeated several times. The product is maintained at +4° C., groundin the presence of pentane, the insoluble part is filtered, rinsed anddried. 6.99 g of sought product is obtained. NMR 1H (300 MHz, CDCl₃-d6,ppm)

1.09 (s, 3H), 1.11 (s, 3H), 1.35 (s, 3H), 1.36 (s, 1H), 1.50 to 1.90 (m,8), 2.23 (s, 3H), 2.24 (s, 3H), 2.76 (s, 3H), 3.28 (d, 1H, J=_Hz), 3.33(d, 1H, J=_Hz), 3.63 (s, 3H), 3.64 (s, 3H), 3.54 (m), 3.97 (m), 4.07(m), 4.20 to 4.30 (_(—), 2H), 4.59 (m, _H), 4.82 (m, _H), 5.63 (bs, _H),5.85 (bs, _H), 7.20 (d, 1H, J=_Hz), 7.88 (m, _H).

EXAMPLE 1 (2-propynyloxy)-carbamic 3′ester of7-[[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxamideacid STAGE A: 3-(4-nitrophenylcarbonate) of ethyl7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyrane-3-carboxylate

4 g of the product of preparation 1 is dissolved under argon in 80 ml ofmethylene chloride. 2.15 g of dimethylaminopyridine and at 0° C. 2 g of4-nitrophenylchloroformate are added. Agitation is carried out for 1hour at 0° C. The methylene chloride is evaporated and the soughtproduct is obtained.

STAGE B: ethyl7-[[6-deoxy-5-C-methyl-4-O-methyl-3-O-[[2-propynyloxy)amino]carbonyl]-2-O-(tetrahydro-2H-pyrane-2-yl)alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyrane-3-carboxylate

1.215 g of O-propargylhydroxylamine chlorohydrate is dissolved in 40 mlof dimethylformamide. At 0° C. 0.392 g of sodium hydride (in 50% of oil)is added and agitation is carried out for an hour at this temperature. 4ml of solution of the product prepared in the previous stage indimethylformamide and 940 mg of dimethylaminopyridine are introduced at0° C. into this suspension. Agitation is carried out for 1 hour at 0° C.followed by diluting with a hexane/ethyl acetate mixture (1-2). Theorganic solution is washed with 400 ml of sodium hydrogen sulphatesolution at 10%, dried over sodium sulphate and evaporated to dryness.7.87 g of crude sought product is obtained.

STAGE C:7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyrane-3-carboxamide(2-propynyloxy)-carbamic 3′-ester acid

2 g of the product of the previous stage is dissolved in 50 ml oftetrahydrofurane. The solution obtained is saturated with ammoniumhydroxide at 0° C. for 10 minutes and agitated for 48 hours at ambienttemperature followed by diluting with 100 ml of a hexane/ethyl acetatemixture (1-1). The organic solution is washed with 100 ml of a 1Msodium-hydrogen phosphate solution, then it is dried over magnesiumsulphate and evaporated to dryness. 2 g of the sought product isobtained.

STAGE D:7-[[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxy-2H-1-benzopyrane-3-carboxamide(2-propynyloxy)-carbamic 3′ester acid

2 g of the product of the previous stage and 200 mg ofp-toluene-sulphonic acid are dissolved in 20 ml of methanol. Agitationis carried out for 1 hour followed by diluting with 100 ml ofhexane/ethyl acetate mixture (1-1), washing with a saturated solution ofsodium dihydrogen phosphate, drying and bringing to dryness. 1.6 g ofproduct is obtained which is purified eluting with an 8% methylenechloride/methanol mixture followed by impasting with an ethylether/pentane mixture. 0.574 g of sought product is obtained. NMR 1H(300 MHz, DMSO-d6, ppm)

1.04 (s, 3H), 1.26 (s, 3H), 2.20 (s, 3H), 3.45, (s, 3H), 3.52 (d, 1H),3.56 (m, 1H), 4.14 (m, 1H), 4.46 (m, 2H), 5.20 (m, 1H), 5.59 (bs, 1H),5.77 (d, mobile 1H), 7.22 (d, 1 Hz), 7.83 (d, 1H), 8.71 (m) and 8.96 (m)(mobile 2H's).

EXAMPLE 2 7-[(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxyl]-4-hydroxy-8-methyl-N-[2-(4-morpholinyl)ethyl]-2-oxo-2H-1-benzopyrane-3-carboxamide(2-propynyloxy)-carbamic 3′-ester acid STAGE A:7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyrane-2-yl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-N-[2-(4-morpholinyl)ethyl]-2-oxo-2H-1-benzopyrane-3-carboxamide(2-propynyloxy) carbamic 3′-ester acid

7.5 ml of 2-(4-morpholino)ethylamine is introduced into a solutioncontaining 1 g of the product of stage B of Example 1 in 4 ml oftetrahydrofurane. Agitation is carried out for 24 hours at ambienttemperature followed by diluting with 100 ml of hexane/ethylacetate/tetrahydrofurane (1-4-1), washing with a saturated solution ofsodium dihydrogen phosphate, drying over magnesium sulphate andevaporating to dryness. 1 g of sought product is obtained.

STAGE B: 7-[(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-N-[2-(4-morpholinyl)ethyl]-2-oxo-2H-1-benzopyrane-3-carboxamide(2-propynyloxy)-carbamic 3′-ester acid

0.97 mmoles of the product of the previous stage is dissolved in 10 mlof methanol. 100 mg of p-toluenesulphonic acid is added. Agitation iscarried out for 1 hour at ambient temperature. A further 80 mg ofp-toluenesulphonic acid is added. Agitation is carried out for 3 hoursfollowed by diluting with 50 ml of a hexane/ethyl acetate mixture (1-3),washing with 75 ml of a 1M solution of sodium dihydrogen phosphate,drying over magnesium sulphate and evaporating to dryness. The productis purified by chromatography on silica eluting with a methylenechloride/methanol mixture (91-9). The product obtained is impasted in anethyl ether/pentane mixture. 0.150 g of sought product is obtained. NMR1H (300 MHz, DMSO-d6, ppm)

1.03 (s, 3H), 1.27 (s, 3H), 2.21 (s, 3H), 2.50 (masked, 4H), 2.57 (t,2H), 3.45 (s, 3H), of 3.40 to 3.69 (m, 4H), 4.13 (m, 1H), 4.47 (d, 2H,J=2.5 Hz), 5.20 (dd, 1H, J=3 and 10 Hz), 5.60 (d, 1H, J=2 Hz), 5.77 (d,1H, J=5 Hz), 7.21 (d, 1H, J=9 Hz), 7.84 (d, 1H, J=9 Hz), 9.45 (t, mobile1H), 10.72 (m, mobile 1H).

EXAMPLE 37-[[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-3-[1-(methoxyimino)ethyl]-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic-3′-esteracid STAGE A:7-[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-3-[1-(methoxyimino)ethyl]-8-methyl-2H-1-benzopyran-2-one

A solution containing 1.2 g of the product of Preparation 2 is heated at40° C. in the presence of 0.597 g of potassium acetate and 0.407 mg ofO-methylhydroxyamine hydrochloride. The reaction medium is agitated forone hour and 30 minutes at 40° C., followed by diluting with an ethylacetate/hexane mixture (4-1), washing with 150 ml of a solution ofsodium hydrogen phosphate, rinsing with water, drying, filtering andevaporating to dryness.

STAGE B:7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-3-[1-(methoxyimino)ethyl]-8-methyl-2H-benzopyran-2-one3-(4-nitrophenylcarbonate)

0.390 g of dimethylaminopyridine is added to a solution containing 1.28mmoles of the product of the previous stage and 12 ml ofdichloromethane. 0.319 g of 4-nitrophenyl chloroformate is added.Agitation is carried out for 30 minutes at 0° C. The methylene chlorideis evaporated and the product obtained is dried. 1.218 mmoles of soughtproduct are thus obtained.

STAGE C:7-[[6-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-3-[1-(methoxyimino)ethyl]-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic3′-ester acid

0.240 g of sodium hydride (with 55% of mineral oil) is added to asolution cooled down to 0° C. of 0.655 g of O-propargylhydroxylaminehydrochloride in 6 ml of dimethylformamide. Agitation is carried out for30 minutes at 0° C. and the reaction medium is poured into a solutioncontaining 1.218 mmoles of the product of the previous stage and 6 ml ofDMF in the presence of 0.150 g of dimethylaminopyridine. After one hourat 0° C., the reaction mixture is poured into an ethyl acetate/hexanemixture at 20%, washed with a solution of sodium hydrogen sulphate at10%, with water and with salt water. The solvents are dried andevaporated to dryness. 0.865 g of sought product is obtained.

STAGE D:7-[[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-3-[1-(methoxyimino)ethyl]-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic-3′-esteracid

150 mg of PTSA is added to a solution containing 1.218 mmoles of theproduct of the previous stage and 12 ml of methanol. Agitation iscarried out for one hour at ambient temperature followed by dilutingwith an ethyl acetate/hexane (1-1) mixture and washing with an aqueoussolution of sodium dihydrogen phosphate 1M, then with salt water. Theorganic phase is dried over magnesium sulphate. The solvents areevaporated to dryness. The product obtained is chromatographed elutingwith a dichloromethane/acetone (85-15) mixture, and 0.394 g of productis obtained which is dissolved again in ether and precipitated withpentane. The insoluble part is isolated by filtration and dried underreduced pressure. 0.380 g of sought product is thus obtained.

EXAMPLE 47-[(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy]-3-[1-(ethoxyimino)ethyl]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic3′-ester acid

Operating as previously, the sought product was obtained.

NMR CDCl₃ ppm

1.17 (s)-1.38 (s): 2 CH3 Gem; 1.38 (t): CH3CH2O; 1.61 (s): 4 mobile,2.25 (s)-2.53 (s):

2.57 (t): J=2.5 h—C C—; 2.64 (bs) OH—CH; 3.54 (s): OCH3; 3.61 (d): J=9.5H4 rex; 4.23 (q) slightly deficient CH3—CH2—O; 4.43 (bs): H2eq; 4.57(d): 2H OCH2—C CH; 5.46 (dd): J=2.5 and 9.5 H3 ox; 5.61 (d): J=2.5 H1eq; 7.12 (d): H′6; 7.77 (d): H′5; mobile H's 7.78: 14.15 and 15.11

Absorptions along the spectrum 2.05 (acetone), 4.13, 4.75-4.60-15.67.

EXAMPLE 58-hydroxy-7-[4-hydroxy-3-[1-(methoxyimino)ethyl]-8-methyl-2-oxo-2H-1-benzopyran-7-yl]-10-methoxy-6-oxaspiro[4.5]decan-9-yl[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-(2-propynyloxy)-carbamate

The preparation of this product and that of the starting products usedcan be shown as follows:

Preparation 3:[8R-(8.alpha.,9.alpha,10.beta)]-10-methoxy-6-oxaspiro[4.5]decan-7,8,9-triolSTAGE A:[4S-[4.alpha.,5.alpha.(S*)]]-2,2-dimethyl-5-[(1-hydroxycyclopentyl)methoxymethyl]-1,3-dioxolane-4-methanol

20 ml of a solution of dibromobutane (106 ml of dibromobutane in 200 mlof THF) is introduced into a mixture containing 43 g of magnesium, 100ml of THF and one iodine crystal. The reaction mixture is subjected toultrasound. 1.7 l of THF is added. The remainder of the dibrominatedsolution is added. Agitation is maintained for 2 hours 30 minutes. Asolution containing 80.37 g of delta-lactone of2-0-methyl-3,4-O-(1-methylethylidene)-L-arabinonic acid and 1 liter ofTHF is added at 17° C. Agitation is carried out for approximately 5hours at ambient temperature. The reaction mixture is cooled down to 0°C., a solution saturated in ammonium chloride is added followed bydecanting, drawing off the organic phase and extracting with a solutionof ethyl acetate with 20% heptane. The reaction mixture is washed, driedand evaporated to dryness. 111.85 g of sought product is thus obtained.

STAGE B:[3′-aS-(3′-a.alpha.,7′.alpha,7′a.beta.)]-7′-methoxydihydro-spiro[cyclopentane-1.6′-[6H]-1,3-dioxolo[4,5-c]pyran]-4′(3aH)-one

221 g of pyridine sulphurtrioxide (PySO3) is added to a solutioncontaining 111 g of the product prepared in Stage A and a mixture of aliter of methylene chloride, 1 liter of DMSO, 0.607 l of triethylamine.Agitation is carried out for 2 hours at ambient temperature. Thereaction mixture is poured into an aqueous solution of phosphate acidphosphate, extracted with an ethyl acetate, heptane (1-1) mixturefollowed by drying, filtering and evaporating to dryness. 57.7 g ofsought product is obtained.

STAGE C:[8R-(8.alpha.,9.alpha,10.beta)]-10-methoxy-6-oxaspiro[4.5]decane-7.8,9-triol

157 ml of a 1.5 M solution of dibutylaluminium hydride in toluene isadded at −5° C. to a solution containing 56 g of the product of theprevious stage and 300 ml of THF. Agitation is carried out at −3° C. for1 hour. 1 liter of a 1 M solution of sodium potassium tartrate is added.Agitation is carried out for 15 minutes at ambient temperature. Thereaction medium is extracted with an ethyl acetate-heptane 1-1 mixturefollowed by washing with water, salt water, drying and evaporating todryness. The residue obtained is agitated at 70° C. in the presence of150 ml of a solution of sulphuric acid 0.1 N and 150 ml of water for 2.5hours. The reaction medium is cooled down to ambient temperature, bariumcarbonate is added, and agitation is carried out for 1 hour at ambienttemperature followed by filtering and evaporating to dryness. 49 g ofthe sought product is obtained.

EXAMPLE 58-hydroxy-7-[4-hydroxy-3-[1-methoxyimino)ethyl]-8-methyl-2-oxo-2H-1-benzopyran-7-yl]-10-methoxy-6-oxaspiro[4.5]decan-9-yl[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-(2-propynyloxy)-carbamateSTAGE A:[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-7-[(8,9-dihydroxy-10-methoxy-6-oxaspiro[4.5]decan-7-yl)oxy]-4-(diphenylmethoxy)-8-methyl-2H-1-benzopyran-2-one

45.30 g of diisopropylazodicarboxylate (DIAD) is added dropwise at 0° C.to a mixture of 49 g of the product of preparation 3, 73 g of theproduct of stage B of preparation 2, namely4-(diphenylmethoxy)-7-hydroxy-8-methyl-2H-1-benzopyran-2-one and 59 g oftriphenylphosphine. Agitation is carried out for 1.5 hours at ambienttemperature. 1 equivalent of triphenylphosphine and DIAD is added at 0°C. The solvents are evaporated, taken up in ether and the sought productobtained.

STAGE B:[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-4-(diphenylmethoxy)-7-[[8-hydroxy-10-methoxy-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]decan-7-yl)oxy]-8-methyl-2H-1-benzopyran-2-one

15.21 g of imidazole, 40.1 ml of diisopropylamine and 18.75 g oftriethylsilane chloride are added at 0° C. to a solution containing 48 gof the product of the previous stage and 400 ml of methylene chloride.Agitation is carried out for 1 hour at 0° C., followed by washing with a1 M solution of sodium acid phosphate and rinsing with water and drying.The product obtained is chromatographed on silica eluting with amethylene chloride/acetone 99-1 mixture then with atoluene/tertbutylmethylether mixture. 28.37 g of the sought product isobtained.

STAGE C:[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-4-(diphenylmethoxy)-7-[[10-methoxy-8-[(tetrahydro-2H-pyran-2-yl)oxy]-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]decan-7-yl)oxy]-8-methyl-2H-1-benzopyran-2-one

7.57 ml of 3,4-dihydropyran and 400 mg of paratoluene sulphonic acid areadded to a solution containing 28.1 g of the product of the previousstage and 250 ml of dichloromethane. Agitation is carried out for 1 hourat ambient temperature. Bicarbonate of soda is added and agitated for 20minutes at ambient temperature followed by washing with water, dryingthe organic phases on sodium sulphate. The product obtained ischromatographed on silica eluting with a heptane-ethyl acetate 4,1mixture. 16.81 g of sought product is obtained.

STAGE D:[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-4-hydroxy-7-[[10-methoxy-8-[(tetrahydro-2H-pyran-2-yl)oxy]-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]decan-7-yl)oxy]-8-methyl-2H-1-benzopyran-2-one

A solution of 16.19 g of the product of the previous stage, 150 ml ofTHF, is agitated under a hydrogen atmosphere in the presence of 810 mgof palladium on carbon followed by filtration, and 15.1 g of soughtproduct is obtained.

STAGE E:[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-3-acetyl-4-hydroxy-7-[[10-methoxy-8-[(tetrahydro-2H-pyran-2-yl)oxy]-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]decan-7-yl)oxy]-8-methyl-2H-1-benzopyran-2-one

2.28 ml of acetic anhydride is added to a mixture containing 13.8 g ofthe product of the previous stage and 150 ml of methylene chloride and5.94 g of dimethylaminopyridine (DMAP). Agitation is carried out for onehour at ambient temperature. The reaction medium is treated with a molarsolution of sodium acid phosphate, extracted with methylene chloride,washed with water and dried. 16.21 g of sought product is obtained whichis used as it is in the following stage.

STAGE F:[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-3-acetyl-4-hydroxy-7-[[9-hydroxy-10-methoxy-8-[(tetrahydro-2H-pyran-2-yl)oxy]-6-oxaspiro[4.5]decan-7-yl)oxy]-8-methyl-2H-1-benzopyran-2-one

1.5 equivalent of a 1M solution of tetrabutylammonium fluoride in THF isadded at 0° C. to a solution containing the product of the previousstage and 200 ml of THF. The reaction mixture is kept under agitation atambient temperature for 15 hours. The reaction mixture is poured ontothe heptane-ethyl acetate 30-70 mixture followed by washing with water,filtering and drying. A product is obtained which is used as it is inthe following stage.

STAGE G:[7R-(7.alpha.,8.beta.,9.beta.,10.alpha.)]-4-hydroxy-7-[[9-hydroxy-10-methoxy-8-[(tetrahydro-2H-pyran-2-yl)oxy]-6-oxaspiro[4.5]decan-7-yl)oxy]-3-[1-(methoxyimino)ethyl]-8-methyl-2H-1-benzopyran-2-one

4.6 g of potassium acetate and 3.12 g of O-methylhydroxylaminehydrochloride are added to a solution containing 18.69 mmoles of theproduct of the previous stage and 100 ml of ethanol. Agitation iscarried out for 1.5 hours at ambient temperature. The reaction medium ispoured onto a 1M solution of sodium acid phosphate, extracted with aheptane/ethyl acetate 30-70 mixture followed by washing with water,drying and evaporating to dryness. The product obtained ischromatographed with a heptane-ethyl acetate (1:1) mixture. 6.54 g ofsought product is obtained.

STAGE H: 8-hydroxy-7-[4-hydroxy3-[1-(methoxyimino)ethyl]-8-methyl-2-oxo-2H-1-benzopyran-7-yl]-10-methoxy-6-oxaspiro[4.5]decan-9-yl[7R.(7.alpha.,8.beta.,9.beta.,10.alpha.)]-(2-propynyloxy)-carbamate

1) 3.70 g of DMAP and 3.05 g of para-nitrobenzene chloroformiate isintroduced at 0° C. into a solution containing 6.37 g of the product ofthe previous stage and 70 ml of dichloromethane. Agitation is carriedout for 1 hour at 0° C.

2) 2.3 g of sodium hydride is added at 0° C. to a solution containing6.26 g of propargylhydroxylamine hydrochloride and 50 ml of DMF.Agitation is carried out for 1 hour at 0° C. The solution (1) isconcentrated to dryness. The residue obtained is dissolved in 50 ml ofDMF. 1.42 g of DMAP is added. The solution (2) is added at 0° C. to thesolution thus obtained. Agitation is carried out for 1 hour at 0° C. Thereaction medium is treated with sodium acid phosphate, washed withwater, dried and concentrated to dryness. The residue obtained isdissolved in 100 ml of methanol. 2.1 g of PTSA is added and agitation iscarried out at ambient temperature. The product obtained ischromatographed eluting with toluene and then with a toluene-isopropylether 92-8 mixture. The product is dispersed under ultrasound in anisopropyl ether-pentane mixture. The sought product is obtained.

NMR spectrum: CDCl₃ ppm

1.30 to 2.00 CH₂ cycle 2.20 (s) C₆H₅—Me 2.50 (s) N═C—Me 2.56 (t)O—CH₂—C≡CH 4.57 (d) . . . . . . . . . . . . . . . .↑ 3.55 (s) C—OMe 3.65(d, J=8) H₄ax 4.00 (s) ═N—OMe 4.38 (sl) H₂eq 5.37 (dd) H₃ax 5.51 (d)H1eq 7.00 (d) H6′ 7.66 (d) H5′ 8.19 (bs) NH

Preparation 4

20.4 g of 2-0-methyl-3,4-0-(1-methylethyledene)L-arabinose is dissolvedunder an argon atmosphere in 200 ml of tetrahydrofurane. 200 ml of a 2 Msolution of allylmagnesium bromide in tetrahydrofurane is added at 0° C.under argon. The solution is agitated for 1 hour at 0° C. The reactionmedium is cooled down to −15° C. and is diluted with 100 ml of heptane.In order to neutralize the excess magnesium, 300 ml of an aqueoussolution of sodium hydrogen sulphate at 10% is added dropwise. Theorganic phase is separated and the aqueous phase is extracted with amixture of heptane 1/ethyl acetate 2. The organic phases are combined,dried over magnesium sulphate and evaporated to dryness. 22.96 g ofsought product is obtained.

Yield: 94%

22.96 g of the product of the previous stage is dissolved under an argonatmosphere in 175 ml of dimethylformamide. 14.88 g of imidazole isadded, then 23.31 ml of diphenylterbutylsilyl chloride is added dropwiseat 0° C. under argon. The solution is agitated for 30 minutes at 0° C.The reaction medium is diluted with 400 ml of a heptane 1/ethyl acetate2 mixture. The organic phase is washed twice with 200 ml of a 1 molaraqueous solution of sodium dihydrogen phosphate, dried over magnesiumsulphate and evaporated to dryness. 45 g of resin product is obtainedwhich is purified by chromatography on silica eluting with a heptane4/ethyl acetate 1 mixture. 39.5 g of sought product is obtained.

Yield: 85%

25.1 g of pyridinium chlorochromate is suspended in 200 ml of methylenechloride. 53.8 g of 4 Å molecular sieve is then added. 39.5 g of theproduct of the previous stage in solution in 100 ml of methylenechloride is then introduced into this suspension in one go. Agitation iscarried out for 3 hours. The suspension is filtered followed by elutingwith a methylene chloride 3% methanol mixture. The filtrate isevaporated to dryness. The residue obtained (35 g) is filtered on silicaeluting with the heptane 4/ethyl acetate 1 mixture.

32.9 g of sought product is obtained.

Yield: 87%

32.5 g of the product of the previous stage is dissolved in 250 ml oftetrahydrofurane. 60 ml of a methylmagnesium bromide solution in ether(3M) is added dropwise under argon at −5° C. Agitation is carried outfor 1 hour at ambient temperature. The excess magnesium is neutralizedat 0° C. with an aqueous solution of sodium hydrogen sulphate at 10%.200 ml of a heptane 1/ethyl acetate 2 mixture is added. The organicphase is washed with 200 ml of an aqueous solution of sodium dihydrogenphosphate (M), dried over magnesium sulphate and evaporated to dryness.The product obtained is impasted in 200 ml of pentane/ether. 16.9 g ofsought product is obtained.

Yield: 64%

16.9 g of the product of the previous stage is dissolved in 150 ml oftetrahydrofurane. 68 ml of a molar solution of tetrabutylammoniumfluoride in tetrahydrofurane is added dropwise under argon at 0° C.Agitation is carried out for 30 minutes at ambient temperature. 200 mlof a heptane 1/ethyl acetate 2 mixture is added. The organic phase iswashed with 200 ml of a molar aqueous solution of sodium dihydrogenphosphate, dried over magnesium sulphate and evaporated to dryness. Thecrude product is purified by chromatography on silica eluting with amethylene chloride 95/methanol 5 mixture. 10.1 g of sought product isobtained.

10.15 g of the product of the previous stage is dissolved in 103 ml ofmethylene chloride. 55 ml of triethylamine and 103 ml ofdimethylsulphoxide stored on molecular sieve are added under argon atambient temperature. The solution is cooled down to approximately 5° C.with an ice-water bath and 19.77 g of pyridine sulphurtrioxide is addedin fractions without the temperature exceeding 15° C. Agitation iscarried out for 1 hour. The reaction medium is poured into 1 liter of amolar aqueous solution of sodium dihydrogen phosphate, the aqueous phaseis extracted twice with a heptane 1/ethyl acetate 2 mixture. The organicphase is washed with water, dried over magnesium sulphate and evaporatedto dryness. The crude product crystallizes and is impasted in pentane.6.8 g of sought product is obtained.

Yield: 68%

5.3 g of the product of the previous stage is dissolved in 30 ml oftetrahydrofurane. 13.85 ml of DIBAL is added under argon at −6° C. After1 hour 30 minutes of agitation at 0° C., the reaction is terminated. Thereaction medium is poured into 100 ml of a 1M solution of sodiumpotassium tartrate; the aqueous phase is extracted with a heptane1/ethyl acetate 2 mixture. The organic phase is washed with 150 ml of anaqueous solution of sodium hydrogen sulphate at 10%, dried overmagnesium sulphate and evaporated to dryness.

5.5 g of sought product is obtained.

Yield: Quantitative

STAGE H:

5.5 g of the product of the previous stage is emulsified in 32 ml of asolution of sulphuric acid at 0.05 N. After 1 hour 30 minutes of heatingat 70° C., the reaction is terminated. The reaction medium is left toreturn to ambient temperature and is neutralized with 0.6 g of bariumcarbonate. The suspension is agitated for one hour at ambienttemperature (pH=7), then filtered and evaporated to dryness. To dry theproduct, two distillations with toluene are carried out followed bydrying and 4.4 g of sought product is obtained.

Yield: 96%

EXAMPLE 67-[[6-deoxy-4-O-methyl-5-C-(2-propenyl)-3-0-[[(2-propynyloxy)amino]carbonyl]-.beta.-D-gulopyranosyl]oxy]-4-hydroxy-8-methyl-3-[1-[(2-propynyloxy)imino]ethyl]-2H-1-benzopyran-2-oneand7-[[6-deoxy-4-O-methyl-5-C-(2-propenyl)-3-0-[[(2-propynyloxy)amino]carbonyl]-.beta.-D-gulopyranosyl]oxy]-4-hydroxy-3-[1-(methoxyimino)ethyl]-8-methyl-2H-1-benzopyran-2-one

4.4 g of the product of preparation 4 in solution is dissolved in 100 mlof methylene chloride. 7.33 g of coumarine(7-hydroxy-3-[(methoxyimino)methyl]-8-methyl-4-(2-propenyloxy)-2H-1-benzopyran-2-one)prepared as indicated in preparation 8 of the international PatentApplication WO 9747634 and 6.29 g of triphenylphosphine are added underargon at ambient temperature. The suspension is cooled down to 0° C.3.73 ml of DEAD is added dropwise. The suspension is agitated for 1 houris added at ambient temperature. A further 6.06 g of triphenylphosphineand at 0° C. 3.11 ml of DEAD are added. After 1 hour of agitation atambient temperature, 50 ml of pentane is added to precipitate thereduced DEAD. The suspension is filtered, the filtrate is evaporated todryness and purified on silica with the eluent mixture toluene at 3%then 6% isopropyl alcohol. 7.1 g of product is obtained. The product isfiltered on silica 60 eluting with an ether/heptane mixture then withether. 6.13 g of sought product is obtained.

6 g of the product of the previous stage is dissolved in 75 ml oftetrahydrofurane. 3.86 g of carbonyldiimidazole is added and thereaction is heated for 1 hour under reflux. The reaction medium isdiluted with 100 ml of heptane 1/ethyl acetate 2 mixture. The organicphase is washed with an aqueous solution of sodium hydrogen sulphate at10%, dried over magnesium sulphate and evaporated to dryness.

4.94 g of sought product is obtained.

4.94 g of the product of the previous stage is dissolved in 120 ml oftetrahydrofurane. 8.44 ml of diisopropylamine is added at 0° C., 1.05 gof palladium tetrakistriphenylphosphine. Agitation is carried out for 20minutes at 0° C. The reaction medium is diluted with 50 ml of a heptane1/ethyl acetate 2 mixture. The organic phase is washed with an aqueoussolution of sodium hydrogen sulphate at 10%, dried over magnesiumsulphate and evaporated to dryness. 5.5 g of crude product is obtainedwhich is purified on silica eluting with a methylene chloride mixturewith 2% acetone.

3.1 g of sought product is obtained.

0.65 g of the product of the previous stage is dissolved in 6.5 ml ofpyridine dried over potassium. 1.5 g of propargylhydroxylaminehydrochloride and 0.149 of lithium perchlorate are added at ambienttemperature. Agitation is carried out at ambient temperature for 48hours followed by diluting with a heptane 1/ethyl acetate 2 mixture, andthe organic phase is washed with a sodium hydrogen sulphate solution at10%, dried over magnesium sulphate. 1.8 g of product is obtained whichis purified by chromatography on silica eluting with the eluent mixturemethylene chloride 80/terbutylmethylether 20.

200 mg of 3-isomer sought product and 500 mg is 2-isomer is obtained.

0.5 g of the 2-isomer obtained in the previous stage is dissolved in 10ml of methylene chloride under an argon atmosphere. 100 μl of DBU isadded. Agitation is carried out for 24 hours at ambient temperaturefollowed by diluting in 50 ml of a heptane 1/ethyl acetate 3 mixture andthe organic phase is washed with a 1 M solution of sodium dihydrogensulphate, dried over magnesium sulphate and evaporated to dryness. Theproduct obtained previously is dissolved in 5 ml of ethanol. 0.72 g ofmethylhydroxylamine hydrochloride and 0.94 g of sodium acetate are addedat ambient temperature. The reaction medium is agitated for 5 hours atambient temperature followed by diluting in 50 ml of heptane 1/ethylacetate 3 mixture and the organic phase is washed with a 1 M solution ofsodium dihydrogen sulphate, dried over magnesium sulphate and evaporatedto dryness. 0.45 g of crude product is obtained which is purified bychromatography on silica with the eluent mixture methylene chloride80/20 terbutylmethylether 20.

100 mg of sought product is obtained.

Preparation 5

20.4 g of 2-0-methyl-3,4-0(1-methylethylidene)L-arabinose is dissolvedunder argon in 250 ml of tetrahydrofurane. 100 ml of a 1 M solution ofvinylmagnesium bromide in tetrahydrofurane then 200 ml of a 1.7 Mmagnesium chloride solution in tetrahydrofurane; 0.34 moles are added at0° C. under argon. The solution is agitated for 1 hour at ambienttemperature. The reaction medium is cooled down to −15° C. and dilutedwith 100 ml of heptane. In order to neutralize the excess magnesium, 300ml of a mixture of 20% of a molar aqueous solution of sodium dihydrogenphosphate in tetrahydrofurane is added. The magnesium salts precipitate.200 ml of a heptane 1/ethyl acetate 2 mixture and 150 ml of a 10%solution of sodium hydrogen sulphate are added. The organic solution isdried over magnesium sulphate and evaporated to dryness. 19.3 g ofsought product is obtained.

Yield: 83%

19.3 g of the product of the previous stage is dissolved in 150 ml ofdimethylformamide. 10.8 g of imidazole is added, then at 0° C. underargon, 23.4 ml of diphenylterbutylsilyl chloride is added dropwise for30 minutes. The solution is agitated for 30 minutes at 0° C. Thereaction medium is diluted with 400 ml of a heptane 1/ethyl acetate 2mixture. The organic phase is washed with a 1 M aqueous solution ofsodium dihydrogen phosphate, dried over magnesium sulphate andevaporated to dryness. 30.2 g of resin product is obtained which ispurified by chromatography on silica eluting with the heptane 4: ethylacetate 1 mixture. 30.2 g of sought product is obtained. Yield: 77%

19.1 g of pyridinium chlorochromate is dissolved in 250 ml of methylenechloride. Then 40 g of 4 Å molecular sieve is added. 28.19 g of theproduct of the previous stage in solution in 100 ml of methylenechloride is introduced into this suspension in one go. After 4 hours ofagitation at ambient temperature, the reaction is finished. The reactionmedium is filtered. The filtrate is evaporated to dryness. The productobtained is chromatographed on silica eluting with a heptane/ethylacetate 6-1 mixture. 10.5 g of sought product is obtained. Yield 36%.

10 g of the product of the previous stage is dissolved in 100 ml oftetrahydrofurane. 14 ml of the 3 M solution of methylmagnesium bromidein ether is added dropwise under argon at −5° C. Agitation is carriedout for 30 minutes at 0° C., the excess magnesium is neutralized with anaqueous solution of sodium hydrogen sulphate at 10%. 200 ml of a heptane1/ethyl acetate 2 mixture is added. The organic phase is washed with 200ml of a molar aqueous solution of sodium dihydrogen phosphate, driedover magnesium sulphate and evaporated to dryness. The crude product ispurified on silica eluting with a heptane 4/ethyl acetate 1 mixture. Theproduct obtained is impasted in pentane. 2.76 g of sought product isobtained. Yield 27%

2.79 g of the product of the previous stage is dissolved in 15 ml oftetrahydrofurane. 11.8 ml of a molar solution of tetrabutylammoniumfluoride in tetrahydrofurane is added dropwise under argon at 0° C.Agitation is carried out for 1 hour at ambient temperature is added. 200ml of a heptane 1/ethyl acetate 2 mixture. The organic phase is washedwith 200 ml of a molar aqueous solution of sodium dihydrogen phosphate,dried over magnesium sulphate and evaporated to dryness. The crudeproduct is purified by chromatography of silica eluting with a methylenechloride mixture with 5% methanol. 1.2 g of sought product is obtained.Yield: 86%

1.2 g of the product of the previous stage is dissolved in 12.5 ml ofmethylene chloride. 6.67 ml of triethylamine and 12.5 ml ofdimethylsulphoxide stored on molecular sieve are added under argon at 0°C. The solution is cooled down to approximately 5° C. with an ice-waterbath and 2.39 g of pyridine sulphurtrioxide is added by fractionswithout the temperature exceeding 15° C. After 1 hour of agitation atambient temperature, the reaction is terminated. Agitation is carriedout for 1 hour at ambient temperature. The reaction medium is pouredinto 100 ml of a molar aqueous solution of sodium dihydrogen phosphate,the aqueous phase is extracted twice with a heptane 1/ethyl acetate 2mixture. The organic phase is washed with water, dried over magnesiumsulphate and evaporated to dryness. The product obtained is impasted inpentane. 0.75 g of sought product is obtained. Yield: 59%

0.73 of the product of the previous stage is dissolved in 30 ml oftetrahydrofurane. 2.5 ml of a 1.5 M solution of DIBAL in toluene isadded under argon at −6° C. Agitation is carried out for 1 hour 30minutes at −6° C. The reaction medium is poured into a 1M solution ofsodium potassium tartrate; the aqueous phase is extracted with a heptane1/ethyl acetate 2 mixture. The organic phase is washed with an aqueoussolution of sodium hydrogen sulphate at 10%, dried over magnesiumsulphate and evaporated to dryness. The product obtained is impasted inpentane. 0.95 g of sought product is obtained. Quantitative yield.

0.9 g of the product of the previous statge is emulsified in 5 ml of asolution of sulphuric acid at 0.05 N. After 1 hour of heating at 70° C.,the reaction is terminated. The reaction medium is left to return toambient temperature, then extracted with pentane and the aqueous phaseis neutralized with 0.1 g of barium carbonate. The suspension isagitated for one hour at ambient temperature (pH=7), then filtered andevaporated to dryness. In order to dry the product, two distillationsare carried out with toluene, followed by solubilizing in methylenechloride, drying the solution over magnesium sulphate and evaporating todryness. 0.5 g of sought product is obtained. Yield 86%.

EXAMPLE 77-[[6deoxy-5-C-ethenyl-4-O-methyl-3-O-[[(2-propynyloxy)amino]carbonyl]-.beta.-D-gulopyranosyl]oxy]-4-hydroxy-3-[1-(methoxymino)ethyl]-8-methyl-2H-1-benzopyran-2-one

0.5 g of the product of preparation 5 is dissolved in 17 ml of methylenechloride. 0.89 g of coumarine prepared as indicated in the InternationalPatent Application WO9747634 and 0.76 g of triphenylphosphine are addedat ambient temperature under argon. The suspension is cooled down to 0°C., 0.45 ml of DEAD is added dropwise. The suspension is agitated for 1hour at ambient temperature. 0.63 g of triphenylphosphine is added againand at 0° C., 0.37 ml of DEAD. A yellow solution is obtained. After 1hour of agitation at ambient temperature, 10 ml of pentane is added toprecipitate the reduced DEAD. The suspension is filtered, the filtrateis evaporated to dryness and purified by chromatography on silica withthe eluent mixture toluene 97/isopropyl alcohol 3 (the elution isfinished with 6%). The product obtained in a mixture is then filtered onsilica 60 eluting with a heptane 1/ether 2 mixture then ether. 0.55 g ofwhite crystals is obtained. Yield: 47%.

0.55 g of the product of the previous stage is dissolved in 7 ml oftetrahydrofurane. 0.364 g of carbonyldiimidazole is added and thereaction mixture is heated for 1 hour under reflux. The reaction mediumis diluted with 40 ml of heptane 1/ethyl acetate 2 mixture. The organicphase is washed with 50 of an aqueous solution of sodium hydrogensulphate at 10%, dried over magnesium sulphate and evaporated todryness. 0.5 g of sought product is obtained. Yield: 88%

0.5 g of the product of the previous stage is dissolved in 12 ml oftetrahydrofurane. 0.82 ml of diisopropylamine and at 0° C., 0.11 g ofpalladium tetrakistriphenylphosphine (0.1 equivalent) are added.Agitation is carried out for 20 minutes at 0° C. The reaction medium isdiluted with 50 ml of a heptane 1/ethyl acetate 2 mixture. The organicphase is washed with 50 ml of an aqueous solution of sodium hydrogensulphate at 10%, dried over magnesium sulphate and evaporated todryness. 0.58 g of crude product is obtained which is purified bychromatography on silica eluting with a heptane 3/ethyl acetate 1mixture. 0.257 g of sought product is obtained. Yield: 57%.

0.257 g of the product from the previous stage is dissolved in 2.5 ml ofpyridine dried over potassium. 0.58 g of propargylhydroxylaminehydrochloride and 0.057 g of lithium perchlorate are added. The reactionmedium is agitated for 48 hours at ambient temperature followed bydiluting with a heptane 1/ethyl acetate 2 mixture, and the organic phaseis washed with a solution of sodium hydrogen sulphate at 10%, dried overmagnesium sulphate. 0.28 g of sought product is obtained. The crudeproduct obtained is dissolved in 5 ml of ethanol, 0.45 h ofmethylhydroxylamine hydrochloride and 0.58 g of sodium acetate areadded. The reaction medium is agitated for 5 hours at ambienttemperature followed by diluting with a heptane 1/ethyl acetate 2mixture and the organic phase is washed with a sodium dihydrogenphosphate (1 M) solution, dried over magnesium sulphate and evaporatedto dryness. 0.3 g of crude product is obtained which is purified bychromatography on silica eluting with a methylene chloride 80/ethylacetate 19/acetic acid 1 mixture. 0.090 g of sought product is obtained.Yield: 31%.

Preparation 6

10.5 g is dissolved in 110 ml of tetrahydrofurane. 329 ml of a 0.135 Msolution of zinc tetraborohydride in ether is added under argon at −6°C. Agitation is maintained for about 30 minutes without an ice bath, thereaction is then terminated. A solution of sodium dihydrogen phosphate(M) is added. The aqueous phase is extracted with a heptane 1/ethylacetate 2 mixture. The organic phase is dried over magnesium sulphateand evaporated to dryness. 10.5 g of sought product is obtained which ispurified by chromatography eluting with a heptane 4/ethyl acetate 1mixture. 8.75 g of sought product is obtained. Yield: 83%

8.75 g of the product of the previous stage is dissolved in 100 ml oftetrahydrofurane. 37 ml of a molar solution of tetrabutylammoniumfluoride in tetrahydrofurane is added under argon at 0° C. After 30minutes of agitation at 0° C., 200 ml of a heptane 1 ethyl acetate 2mixture is added. The organic phase is washed with 200 ml of a molaraqueous solution of sodium dihydrogen phosphate, dried over magnesiumsulphate and evaporated to dryness. The crude product (10.5 g) ispurified by chromatography eluting the methylene chloride with 20% ofacetone mixture on silica. 3.6 g of sought product is obtained.

Yield: 78%.

3.57 g of the product of the previous stage is dissolved in 38 ml ofmethylene chloride. 20.5 ml of triethylamine and 38 ml ofdimethylsulphoxide are added under argon at ambient temperature. Thesolution is cooled down to approximately 5° C. and 7.6 g of pyridinesulphur trioxide is added without the temperature exceeding 15° C.Agitation is carried out for 2 hours. The reaction medium is poured into500 ml of a molar aqueous solution of sodium dihydrogen phosphate, theaqueous phase is extracted twice with a heptane 1/ethyl acetate 2mixture. The organic phase is washed twice with 500 ml of water, driedover magnesium sulphate and evaporated to dryness. The crude productcrystallizes and is impasted in pentane. 1.92 g of sought product isobtained. Yield: 56%

1.9 g of the product of the previous stage is dissolved in 10 ml oftetrahydrofurane. 6.66 ml of 1.5 M solution of DIBAL in toluene is addedunder argon at 0° C. Agitation is carried out for 1 hour 30 minutes. Thereaction medium is poured into 100 ml of a 1M solution of sodiumpotassium tartrate; the aqueous phase is extracted with a heptane1/ethyl acetate 2 mixture. The organic phase is washed with 150 ml of anaqueous solution of sodium hydrogen sulphate at 10%, dried overmagnesium sulphate and evaporated to dryness.

1.9 g of sought product is obtained.

Yield: Quantitative

1.95 g of the product of the previous stage is emulsified in 11.5 ml ofa sulphuric acid solution at 0.05 N followed by heating for 1 hour 30minutes at 70° C. and left to return to ambient temperature. Thereaction medium is neutralized with 0.3 g of barium carbonate. Thesuspension is agitated for one hour at ambient temperature (pH=7), thenfiltered and evaporated to dryness. In order to dry the product, twodistillations with toluene are carried out. Acter drying (overnight at40° C. in the presence of P₂O₅), 1.2 g of sought product is obtained.

Yield: Quantitative

EXAMPLE 87-[(6-deoxy-6-C-methyl-4-O-methyl-3-O-[[(2-propynyloxy)-amino]carbonyl]-.alpha.-L-mannopyranosyl)oxyl]-4-hydroxy-8-methyl-3-[1-[(2-propynyloxy)imino]ethyl]-2H-1-benzopyran-3-yl]-2-one7-[(6-deoxy-6-C-methyl-4-O-methyl-3-O-[[(2-propynyloxy)-amino]carbonyl]-.alpha.-L-mannopyranosyl)oxyl-3-[1-(methoxyimino)ethyl]8-methyl-2H-1-benzopyran-3-yl]-2one

1.16 g of the product of preparation 6 is dissolved in 25 ml ofmethylene chloride. 2.19 g of coumarine 7-hydroxy-3[(methoxyimino)methyl]-8-methyl-4-(2-propenyloxy)-2H-1-benzopyran-2-one prepared asindicated in the International Patent Application WO9747634 and 1.89 gof triphenylphosphine are added under argon at ambient temperature. Thesuspension is cooled down to 0° C., 1.12 ml of DEAD is added dropwise.The suspension is agitated for 1 hour at ambient temperature. A further1.58 g of triphenylphosphine and, at 0° C., 0.93 ml of DEAD are added.After 1 hour of agitation at ambient temperature, 50 ml of pentane isadded to precipitate the reduced DEAD. The suspension is filtered, thefiltrate is evaporated to dryness and purified by chromatography onsilica eluting with a toluene mixture with 3% isopropyl alcohol. 0.870 gof white crystals and 0.850 g of a mixture containing traces of reducedDEAD are obtained. The product is filtered rapidly on 100 g of silica 60eluting with ether. 0.4 g of sought product is obtained. Total weight:1.27 g. Yield: 44%

1.27 g of the product of the previous stage is dissolved in 10 ml oftetrahydrofurane. 0.85 g of carbonyldiimidazole is added followed byheating for 1 hour under reflux. The reaction medium is diluted with 50ml of a heptane 1/ethyl acetate 2 mixture. The organic phase is washedtwice with 50 ml of an aqueous solution of sodium hydrogen sulphate at10%, dried over magnesium sulphate and evaporated to dryness. 1.4 g ofsought product is obtained. Yield: Quantitative

0.6 g of the product of the previous stage is dissolved in 6.5 ml ofpyridine dried over potassium. 1.5 g of propargylhydroxylaminehydrochloride and 0.149 of lithium perchlorate are added at ambienttemperature. Agitation is carried out for 48 hours at ambienttemperature followed by dilution with a heptane 1/ethyl acetate 2mixture and the organic phase is washed with a sodium hydrogen sulphatesolution at 10%, dried over magnesium sulphate. 1.8 g of product isobtained which is chromatographed on silica eluting with a methylenechloride 80/ethyl acetate 19/acetic acid 1 mixture. 186 mg of isomer-3sought product is obtained, 400 mg of isomer-2.

Yield: 74% opening of the carbonate of which 30% is isomer-3.

0.4 g of the product of the previous stage (isomer-2) is dissolved in 10ml of methylene chloride. 100 μl of DBU is added. Agitation is carriedout for 24 hours at ambient temperature followed by diluting with aheptane 1/ethyl acetate 2 mixture and the organic phase is washed with a1 M solution of sodium dihydrogen phosphate, dried over magnesiumsulphate and evaporated to dryness. In a 100 ml flask, 0.4 g of themixture previously obtained is dissolved in 10 ml of ethanol. 0.59 g ofmethylhydroxylamine hydrochloride and 0.76 g of sodium acetate are addedat ambient temperature. The reaction medium is agitated for 5 hours atambient temperature followed by diluting with a heptane 1/ethyl acetate2 mixture, and the organic phase is washed with a 1 M solution of sodiumdihydrogen phosphate, dried over magnesium sulphate and evaporated todryness. 0.45 g of crude product is obtained which is purified on silicawith a methylene chloride 80/ethyl acetate 19/acetic acid 1 eluentmixture. Only the expected isomer-3 is isolated. 0.140 g of soughtproduct is obtained.

Yield: 37%

Preparation 7

26.8 g of product is dissolved under argon in 250 ml oftetrahydrofurane. 400 ml of a 1 M solution of ethylmagnesium bromide intetahydrofurane is added dropwise at 0° C. under argon. The solution isagitated for 2 hours at ambient temperature. The reaction medium iscooled down to 0° C. and is diluted with 100 ml of heptane. In order toneutralize the excess magnesium, 300 ml of a molar aqueous solution ofsodium dihydrogen phosphate is added dropwise. Magnesium saltsprecipitate. 200 ml of a heptane 1/ethyl acetate 2 mixture and 150 ml ofa 10% solution of sodium hydrogen sulphate are added. The organicsolution is dried over magnesium sulphate and evaporated to dryness. 29g of product is obtained which is chromatographed on silica eluting witha heptane 1/ethyl acetate 4 mixture. 17 g of sought product is obtained.Yield 52%.

16.7 g of the product of the previous stage is dissolved under argon in150 ml of dimethylformamide. 10.07 g of imidazole is added then 19.23 mlof diphenylterbutylsilyl chloride is added dropwise at 0° C. under argonover 30 minutes.

The solution is agitated for 1 hour 30 minutes at ambient temperature.

The reaction medium is diluted with 400 ml of heptane 1/ethyl acetate 2mixture. The organic phase is washed with a molar aqueous solution ofsodium dihydrogen phosphate, dried over magnesium sulphate andevaporated to dryness. 38 of product is obtained which is purified bychromatography on silica eluting with a methylene chloride mixture with10% of acetone. 33.23 g of sought product is obtained. Yield:Quantitative

22.57 g of pyridinium chlorochromate 0.104 moles is suspended in 300 mlof methylene chloride. Then 110 g of molecular 4Å sieve is added. 33 gof the product of the previous stage in solution in 100 ml of methylenechloride is introduced into this suspension. After 3 hours of agitationat ambient temperature, the suspension is filtered. The filtrate isevaporated to dryness. The residue obtained (35 g) is purified on silicawith the eluent mixture heptane 4/ethyl acetate 1.27 g of sought productis obtained. Yield 83%.

16.5 g of the product of the previous stage is dissolved in 150 ml oftetrahydrofurane. 17.52 ml of a 3M solution of methylmagnesium bromidein ether is added dropwise under argon at −5° C. Agitation is carriedout for 1 hour at ambient temperature. The excess magnesium isneutralized at 0° C. with a molar aqueous solution of sodium dihydrogenphosphate. 200 ml of a heptane 1/ethyl acetate 2 mixture is added. Theorganic phase is washed with 200 ml of a molar aqueous solution ofsodium dihydrogen phosphate, dried over magnesium sulphate andevaporated to dryness. The product obtained is impasted in pentane.14.85 g of sought product is obtained. Yield: 87%

14.85 g of the product of the previous stage is dissolved in 150 ml oftetrahydrofurane. 33 ml of a molar solution of tetrabutylammoniumfluoride in tetrahydrofurane is added dropwise under argon at 0° C.After 30 minutes of agitation at ambient temperature, the reaction isterminated. 200 ml of a heptane 1/ethyl acetate 2 mixture is added. Theorganic phase is washed with 200 ml of a molar aqueous solution ofsodium dihydrogen phosphate, dried over magnesium sulphate andevaporated to dryness. The crude product is purified on silica elutingwith a methylene chloride mixture with 15% of acetone then with 30% ofacetone. 7.85 g of sought product is obtained. Yield: Quantitaitve

7.85 g of the product of the previous stage is dissolved in 82.5 ml ofmethylene chloride. 44.5 ml of triethylamine and 82.5 ml ofdimethylsulphoxide stored on molecular sieve are added under argon atambient temperature. The solution is cooled down to approximately 5° C.with an ice-water bath and 15.8 g of pyridine sulphur trioxide is addedby fractions without the temperature exceeding 15° C. Agitation iscarried out for 1 hour. The reaction medium is poured into 1 liter of amolar aqueous solution of sodium dihydrogen phosphate, the aqueous phaseis extracted with a heptane 1/ethyl acetate 2 mixture. The organic phaseis washed with water, dried over magnesium sulphate and evaporated todryness. The product obtained is impasted in pentane. 5.77 g of soughtproduct is obtained. Yield 80%.

5.46 g of the product of the previous stage is dissolved in 25 ml oftetrahydrofurane. 16.7 ml of a 1.5 M solution of DIBAL in toluene isadded under argon at 0° C. Agitation is carried out for 1 hour 30minutes at 0° C. The reaction medium is poured into 250 ml of a 1 Msolution of sodium potassium tartrate; the aqueous phase is extractedwith a heptane 1/ethyl acetate 2 mixture. The organic phase is washedwith 150 ml of an aqueous solution of sodium sulphate at 10%, dried overmagnesium sulphate and evaporated to dryness. 5.5 g sought product isobtained. Yield: Quantitative

5.5 g of the product of the previous stage is emulsified in 32 ml ofsolution of sulphuric acid at 0.05 N. After one hour 30 minutes ofheating at 70° C., the reaction is terminated. The reaction medium isleft to return to ambient temperature and is neutralized with 0.6 g ofbarium carbonate; the suspension is agitated for one hour at ambienttemperature (pH=7), then filtered on miliporous filter paper andevaporated to dryness. In order to dry the product, two distillationswith toluene are carried out followed by drying at 40° C. in thepresence of P₂O₅. 4.8 g gummy white residue is obtained. Quantitativeyield.

EXAMPLE 97-[(6-deoxy-5-C-ethyl-4-O-methyl-.beta.-D-gulopyranosyl)oxy]-4-hydroxy-8-mehtyl-3-[1-[(2-propynyloxy)imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid7-[(6-deoxy-5-C-ethyl-4-O-methyl-.beta.-D-gulopyranosyl)oxy]-4-hydroxy-3-[1-(methoxyimino[ethyl]-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic3′-ester acid7-[(6-deoxy-5-C-ethyl-4-O-methyl-.beta.-D-gulopyranosyl)oxy]-3-[1(ethoxyimino)ethyl]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

4.8 g of the product of the preparation 7 is dissolved in 100 ml ofmethylene chloride. 9.98 g of coumarine and 7.23 g of triphenylphosphineare added at ambient temperature under argon. The suspension is cooleddown to 0° C., 4.34 ml DEAD is added dropwise. The slightly yellowsuspension is agitated for 1 hour at ambient temperature. A further 6 gof triphenylphosphine and at 0° C. 3.57 ml of DEAD are added. A yellowsolution is obtained. After 1 hour of agitation at ambient temperature,50 ml of pentane is added in order to precipitate the reduced DEAD. Thesuspension is filtered, the filtrate is evaporated to dryness andpurified on 1.750 kg of silica 60 with an eluent mixture of toluene at3% then 6% isopropyl alcohol. 10 g of white crystals containing tracesof reduced DEAD is obtained. The product is filtered rapidly on silica60 with an eluent mixture heptane 1/ethyl acetate 2 in order toeliminate the reduced DEAD, then with a methylene chloride 95/methanol 5mixture in order to obtain 7.3 g of expected product. Yield: 58%

7.2 g of the product of the previous stage is introduced into 100 ml ofTHF. 4.41 g diimidazole carbonate is added followed by heating for onehour under reflux. The reaction medium is poured into 150 ml of ahydrogen phosphate solution at 10% and extracted with a mixture ofhexane ethyl acetate followed by drying, and 7.1 g of sought product isobtained.

7.1 g of product is dissolved in 100 ml of tetrahydrofurane. 0.7 g ofpalladium on carbon is added followed by subjecting to a hydrogenatmosphere. After 3 hours of agitation, the reaction is terminated. Thereaction medium is filtered and the filtrate is evaporated to dryness.The product is recrystallized in an ether/pentane mixture. 4.75 g ofsought product is obtained. Yield: 95%

1.5 g of product obtained in the previous stage is dissolved in 25 ml ofmethylene chloride. 0.99 g of dimethylaminopyridine and dropwise underargon at 0° C., 0.38 ml of acetic anhydride are added. After 30 minutesof agitation at 0° C., 95 μl of acetic anhydride and 0.225 g ofdimethylaminopyridine are added. Agitation is carried out for 45minutes. The reaction medium is diluted with 100 ml of heptane 1/ethylacetate 2 mixture. The organic phase is washed twice with 150 ml of a 1M aqueous solution of sodium dihydrogen phosphate, dried over magnesiumsulphate and evaporated to dryness. The expected product is isolated.1.56 g of sought product is obtained. Yield: 93%

1.5 g of the product of the previous stage is dissolved in 15 ml ofpyridine dried over potassium. 3.6 g of propargylhydroxylaminehydrochloride and 0.36 g of lithium perchlorate are added at ambienttemperature. The reaction medium is agitated for 48 hours at ambienttemperature followed by diluting with a heptane 1/ethyl acetate 2mixture, and the organic phase is washed with a solution of sodiumhydrogen sulphate at 10%, dried over magnesium sulphate.

1.8 g of sought product is obtained. 200 mg of this crude product ispurified on silica with an eluent mixture methylene chloride80/terbutylmethylether 20. 90 mg of sought product is obtained, isomer-3and 75 mg of isomer-2. Yield: 77% 55/45 in isomer-3

0.5 g of the product of the previous stage is dissolved in 5 ml ofethanol. 0.85 g of methylhydroxylamine hydrochloride and 0.94 g ofpotassium acetate are added at ambient temperature. The reaction mediumis agitated for 5 hours at ambient temperature followed by diluting witha heptane 1/ethyl acetate 2 mixture, and the organic phase is washedwith a 1 M sodium dihydrogen phosphate solution, dried over magnesiumsulphate and evaporated to dryness. A crude product is obtained which ispurified on silica with the eluent mixture methylene chloride with 20%of terbutylmethylether. 0.095 g of sought product is obtained.

The operation is carried out as indicated in stage F using 0.85 g ofethyl hydroxylamine hydrochloride. 0.103 g of the expected productisomer-3 is obtained.

EXAMPLE 107-[(6-deoxy-5-C-ethyl-4-O-methyl-.beta.-D-gulopyranosyl)oxy]-3-[1-(methoxyimino)propyl]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

0.6 g of the product obtained as in stage C of Example 9 is dissolved in15 ml of methylene chloride. 0.36 g of dimethylaminopyridine anddropwise, under argon at 0° C., 0.20 g of propionic anhydride are added.Agitation is carried out for 30 minutes at 0° C. then for 1 hour atambient temperature. The reaction medium is diluted with 100 ml ofheptane 1/ethyl acetate 2 mixture. The organic phase is washed with a 1M aqueous sodium dihydrogen phosphate solution, dried over magnesiumsulphate and evaporated to dryness. 0.6 g of sought product is obtained.Yield: 68%

0.6 g of the product of the previous stage is dissolved in 6 ml ofpyridine dried over potassium. 1.39 g of propargylhydroxylaminehydrochloride and 0.13 g of lithium perchlorate are added. The reactionmedium is agitated for 48 hours at ambient temperature followed bydiluting with a heptane 1/ethyl acetate 2 mixture and the organic phaseis washed with a solution of sodium hydrogen sulphate at 10%, dried overmagnesium sulphate.

0.56 g of product is obtained which is dissolved in 10 ml of ethanol,1.07 g of methylhydroxylamine hydrochloride and 1.39 g of sodium acetateare added.

The reaction medium is agitated for 5 hours at ambient temperaturefollowed by diluting with a heptane 1/ethyl acetate 2 mixture, and theorganic phase is washed with a 1 M sodium dihydrogen phosphate solution,dried over magnesium sulphate and evaporated to dryness. 0.45 g of crudeproduct is obtained which is purified by chromatography on silicaeluting with a methylene chloride mixture with 20% ofterbutylmethylether. 0.170 g of sought product is obtained. Operating aspreviously, the products corresponding to the following formula werealso prepared:

Operating as previously the following products corresponding to formula(I) were obtained:

R1 R R₅ R₆ R₇ R₂ R₃ Z Y X H CH₃ OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅ CH₃ H OCH₃CH₃ CH₃ H CH₃ H O OC₂H₅ C₂H₅ H OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅ C₂H₅ H OCH₃CH₃ CH₃ H CH₃ H O NH₂ C₂H₅ H OCH₃ CH₃ CH₃ H₃ H OCH₂Bz O NH₂ —CH₂—C═CH₂ HOCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅ —CH₂—C═CH₂ H OCH₃ CH₃ CH₃ H H OCH₂Bz O NH₂

H OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅

H OCH₃ CH₃ CH₃ H CH₃ H O NH₂

H OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅

H OCH₃ CH₃ CH₃ H CH₃ H O NH₂

H OCH₃ CH₃ CH₃ H CH₃ H O NH₂

H OCH₃ CH₃ CH₃ H CH₃ OCH₂Bz O NH₂

H OCH₃ CH₃ CH₃ H CH₃ H O CH₂CH₃

H OCH₃ CH₃ CH₃ H H OCH₂Bz O NH₂

H OCH₃ CH₃ CH₃ H CH₃ H O

—CH₂—C≡CH H OCH₃ CH₃ CH₃ H CH₃ H O CH₂ —CH₂—C≡CH H OCH₃ CH₃ CH₃ H CH₃ HC OC₂H₅ —CH₂—C≡CH H OCH₃ CH₃ CH₃ H CH₃ H O N(CH₂)₂NH₂ —CH₂—C≡CH H OCH₃CH₃ CH₃ H CH₃ H O —NOCH₃

H OCH₃ CH₃ CH₃ H CH₃ H O CH₃

H OCH₃ CH₃ CH₃ H CH₃ H NOCH₃ OC₂H₅

H OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅

H OCH₃ CH₃ CH₃ H CH₃ H O NH₂

H OCH₃ CH₃ CH₃ H CH₃ H O

CH₃—C≡C—CH₂— H OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅ CH₃—C≡C—CH₂— H OCH₃ CH₃ CH₃H CH₃ H O NH₂ N≡C— H OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅ N≡C— H OCH₃ CH₃ CH₃ HCH₃ H O NH₂

H OCH₃ CH₃ CH₃ H CH₃ H O

H OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅ ClCH₂—CH₂— H OCH₃ CH₃ CH₃ H CH₃ H O OC₂H₅ClCH₂—CH₂— H OCH₃ C₂H₅ C₂H₅ H CH₃ H O OC₂H₅

Operating as previously, the following products were prepared:

3-[1-[[(5-chloro-1,2,3-thiadiazol-4-yl)methoxy]imino]ethyl]-7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

3-[1-[(cyanomethoxy)imino]ethyl]-7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

3-[1-[(2-aminoethoxy)imino]ethyl]-7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[[6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3[1-[(2-hydroxyethoxy)imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[(3-piperidinyl)oxy]imino]ethyl]-2H-1-benzopyran-2-one(isomer B) (2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[(3-piperidinyl)oxy]imino]ethyl]-2H-1-benzopyran-2-one(isomer A) (2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[(1-methylethoxy)imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

3-[1-[(cycobutyloxy)imino]ethyl]-7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-(propoxyimino)ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-(2,2,2-trifluoroethoxy)imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[(pentafluorophenyl)methoxy]imino]ethyl]-2H-1-benzopyran-2-one (2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[3-[4-(3-pyridinyl)-1H-imidazol-1-yl]propoxy]imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[2-(1-piperidinyl)ethoxy]-imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[2-(4-morpholinyl)ethoxy]-imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-(methoxyimino)propyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[(2,2,2-trifluoroethoxy)imino)propyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-(prppoxyimino)propyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-3-[1-(ethoxyimino)propyl]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[[6-deoxy-5-C-methyl-4-O-methyl-3-O-[[(2-propynyloxy)amino]carbonyl]-.alpha.-L-lyxo-hexopyranosyl)oxy]-3-[1-(ethoxymethoxy)imino]ethyl]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one

7-[[6-deoxy-5-C-methyl-4-O-methyl-3-O-[[(2-propynyloxy)propynyloxy)amino]carbonyl].alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[(2-methyl-4-thiazolyl)methoxy]imino]ethyl]-2H-1-benzopyran-2-one

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[(2-thiazolyl)methoxy]imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[(3-furanyl)methoxy]imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-[[(3-thienyl)methoxy]imino]ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-3-[1-[[(2-furanylmethoxy)imino]ethyl]-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-3-[1-[[(3,5-dimethyl-isoxazol-4-yl)methoxy]imino]ethyl]-8-methyl-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

7-[(6-deoxy-5-C-methyl-4-O-methyl-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-3-[1-(phenoxyimino)ethyl]-2H-1-benzopyran-2-one(2-propynyloxy)-carbamic 3′-ester acid

methyl[[[1-[7-[[6-deoxy-5-C-methyl-4-O-methyl-3-O-[[(2-propynyloxy)amino]carbonyl]-.alpha.-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl]ethylidene]amino]oxy]acetate

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

Tablets were prepared containing:

Product of Example 1 . . . 150 mg

Excipient s.g.t. . . . 1 g

Detail of excipient: starch, talc, magnesium stearate

Product of Example 5 . . . 150 mg

Excipient s.g.t. . . . 1 g

Detail of excipient: starch, talc, magnesium stearate

Injectable solutions were also prepared from salified products.

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

A—Method of dilutions in liquid medium

A series of tubes is prepared in which the same quantity of sterilenutritive medium is distributed. Increasing quantities of the product tobe studied are distributed into each tube, then each tube is sown with abacterial strain. After incubation for twenty-four hours in an oven at37° C., the growth inhibition is evaluated by transillumination, whichallows the minimal inhibitory concentrations (M.I.C.) to be determined,expressed in micrograms/cm³. Activity in vitro MIC in μg/ml

Ex. 1 Ex. 2 Ex. 3 Ex. 4 Staph. aureus 011HT18 0.04 0.04 0.04 0.04 Staph.epidermidis 0126042 0.04 0.04 0.04 0.15 Staph. coag. negative 012HT5 0.30.04 0.15 0.15 Strepto. pyogene 02A1UC1 0.6 0.3 0.6 0.6 Strepto.pneumoniae 030BI2 0.04 0.08 0.08 0.15 Entero faecium 02D3IP2 0.08 0.61.2 1.2 Entero faecalis 02D2UC5 0.3 1.2 1.2 1.2

B—Inhibition of gyrase B

The products are inhibitors of gyrase B; the dose at 50% of DNAsupercoiling is less than 5 μg/ml.

What is claimed is:
 1. A compound selected from the group consisting ofa compound of the formula

wherein Y is selected from the group consisting of oxygen, ═N—Nalk₁ and═NOalk₂, alk₁ and alk₂ are individually alkyl of 1 to 12 carbon atomsoptionally interrupted by at least one member of the group consisting ofoxygen, sulfur and nitrogen and optionally substituted with at least onemember of the group consisting of halogen, aryl, halogen, aryl,haloaryl, heterocyclic and

Ra and Rb are individually hydrogen or substituted or unsubstitutedalkyl of 1 to 8 carbon atoms or Ra and Rb with the nitrogen to whichthey are attached form a heterocycle which may contain another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen,X is selected from the group consisting of hydrogen, —OH, alkyl andcycloalkyl of up to 12 carbon atoms optionally interrupted by at leastone member of the group consisting of oxygen, nitrogen and sulfur andoptionally substituted with at least one halogen, alkenyl and alkynyl ofup to 12 carbon atoms, heterocycle, —OH, acyloxy, —CN, —NO₂, alkoxy ofup to 12 carbon atoms,

as above, Rc and Rd have the definition of Ra and Rb, Re is alkyl of 1to 12 carbon atoms unsubstituted or substituted, Z is selected from thegroup consisting of hydrogen, halogen and —OH free or esterified oretherified, R₂ is hydrogen or halogen, R₃ is selected from the groupconsisting of hydrogen, halogen and alkyl of 1 to 8 carbon atoms, R ishydrogen or alkyl of 1 to 4 carbon atoms, R₁ is selected from the groupconsisting of hydrogen, —CN, aryl of 6 to 14 carbon atoms and alkyl,cycloalkyl, alkenyl and alkynyl of up to 8 carbon atoms unsubstituted orsubstituted with at least one halogen, R₅ is hydrogen or alkoxy of 1 to4 carbon atoms, R₆ is alkyl or —CH₂—O-alkyl of 1 to 8 alkyl carbon atomsand R₇ is hydrogen or alkyl of 1 to 8 carbon atoms or R₆ and R₇ togetherwith the carbon to which they are attached form a ring of up to 8 carbonatoms and its non-toxic, pharmaceutically acceptable acid additionsalts.
 2. A compound of claim 1 wherein Y is oxygen.
 3. A compound ofclaim 1 wherein Y is NO-alkyl of 1 to 4 carbon atoms.
 4. A compound ofclaim 1 wherein Y is NOC₂H₅.
 5. A compound of claim 1 wherein X is alkylof 1 to 4 carbon atoms.
 6. A compound of claim 1 wherein X is —NH₂.
 7. Acompound of claim 1 wherein X is


8. A compound of claim 1 wherein R₁ is:


9. A compound of claim 1 wherein R is hydrogen.
 10. A compound of claim1 wherein R₃ is methyl.
 11. A compound of claim 1 wherein Z is hydrogen.12. A compound of claim 1 wherein R₂ is hydrogen.
 13. A compound ofclaim 1 wherein R₅ is OCH₃.
 14. A compound of claim 1 wherein R₆ ismethyl.
 15. A compound of claim 1 wherein R₇ is methyl.
 16. A compoundof claim 1 wherein R₇ is ethyl.
 17. A compound of claim 1 wherein R₆ andR₇ form with the carbon atom to which they are attached a cyclopentyl.18. A compound of claim 1 selected from the group consisting of(2-propynyloxy) carbamic acid 3′-ester of7-[[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxamide(2-propynyloxy)-carbamic acid 3′-ester of7-[(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy]-4-hydroxy-8-methyl-N-[2-(4-morpholinyl)ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide(2-propynyloxy)-carbamic acid 3′-ester of7-[[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-3-[1-methoxyimino)ethyl]-8-methyl-2H-1-benzopyran-2-oneand (2-propynyloxy)-carbamic acid 3′-ester of7-[(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy]-3-[1-(ethoxyimino)ethyl]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one.
 19. A compound of claim1 which is (2-propynyloxy)-carbamic acid 3′-ester of7-[(6-deoxy-5-C-ethyl-4-O-methyl-.beta.-D-gulopyranosyl)oxy]-4-hydroxy-3-[1-(methoxyimino)ethyl]-8-methyl-2H-1-benzopyran-2-oneor [7R-(7.alpha., 8.beta., 9.beta., 10.alpha)]-(2-propynyloxy)-carbamateof8-hydroxy-7-[4-hydroxy-7-[4-hydroxy-3-[1-methoxyimino)ethyl]-8-methyl-2-oxo-2H-1-benzopyran-7-yl]-10-methoxy-6-oxaspiro[4.5]decan-9-yl.20. A compound having a formula selected from the group consisting of


21. An antibiotic composition comprising an antibiotically effectiveamount of a compound of claim 1 and a pharmaceutical carrier.
 22. Amethod of treating bacterial infections in warm-blooded animalscomprising administering to warm-blooded animals in need thereof abactericidally effective amount of a compound of claim
 1. 23. A compoundof the formula

wherein R₂, R₃, Z, R₅, R₆ and R₇ are defined as in claim 1, OW is aprotected hydroxy and W′ is alkyl of 1 to 4 carbon atoms or alkoxy of 1to 4 carbon atoms.